Method for preparation of chlorinated methyl pyrazines

ABSTRACT

The direction chlorination of methylpyrazine by heating in a solvent to provide chlorinated 2-methylpyrazine compounds is described. The compounds are useful as intermediates in preparing the therapeutically active (3-aminopyrazinoyl) guanidine products which are effective natriuretic and antikaluretic compounds.

mum tates Patent Inventors Edward J. J. Grabowski Hselin; v Edward W.Tristram, Cranlord; Roger J. Tull, Metuchen, all at N..!. App]. No.766,652 Filed Oct. 10, 1968 Patented Dec. 7, 1971 Assignee Merclir 0:(30., inc.

Rahway, NJ.

METHOD FOR PREPARATION OF CHLORHNATED METHYL PYRAZIINES [50] Field 0tSearch 260/250 [56] References Cited UNITED STATES PATENTS 3,501,4723/l970 Wilcox et al 260/250 3,344,142 9/1967 Powell et al. 260/250Primary Examiner-Nicholas S. Rizzo Attorneys-Erma R. Coutts, Harry E.Westlake, Jr. and l.

Louis Wolk ABSTRACT: The direction chlorination of methylpyrazine byheating in a solvent to provide chlorinated Z-methylpyrazine compoundsis described. The compounds are useful as intermediates in preparing thetherapeutically active (3- aminopyrazinoyl) guanidine products which areeffective natriuretic and antikaluretic compounds.

METHOD FOR PREPARATION OF CHLORTNATED METHYL PYRAZINES This invention isconcerned with novel chlorinated methylpyrazine compounds having atleast two chlorine atoms attached to the methylpyrazine structure.

The novel chlorinated methylpyrazine products of this invention can beillustrated by the structure wherein m represents the numerals 2 throughand n is O or 1, with the proviso that when n is l, the (C C1 group is anuclear substituent.

The novel chlorinated methylpyrazine compounds of this invention havebeen found to be especially useful as intermediates in the preparationof a variety of compounds, particularly in the preparation of the known(3- aminopyrazinoyhquanidine diuretic products which are effective inthe treatment of edematous conditions and especially valuable because oftheir antikaliuretic properties. Some of the products are also useful inthe preparation of pyraziniminocarboxylic acid amides or hydrazidesknown to possess antitubercular and analeptic properties, exhibitingmarked stimulating effects upon the cardiac, circulatory and respiratorysystems.

1t is known, from the work concerning the preparations ofpyrazinoylguanidine compounds that it is difficult to introduce asubstituent in the 5-position in relation to the carbonyl groupparticularly when it is desired to have an amino substituent in thisposition and especially when the 3-position carbon does not carry asubstituent. The novel products of this invention, particularly the2-chloro-3-chloromethylpyrazine compounds are especially useful asintermediates for the preparation of these valuable products as they areeasily converted to the esters of the 3-aminopyrazinoic acid,3,5-diaminopyrazinoic acid or 3,5-diamino-6-chloropyrazinoic acid, theintermediates needed for the preparation of the therapeutically usefulpyrazinoylguanidine diuretic products, the preparation of which from theesters is described in U.S. Pat. No. 3,313,813 which issued Apr. 11,1967.

The trichloromethylpyrazine compounds of this invention have been foundadditionally to be especially suitable intermediates for making thepyrazinamide products described in U.S. Pat. No. 2,149,279 as effectiveagents in the treatment of tuberculosis as well as possessing usefulanaleptic properties.

The novel method for preparing the chlorinated methylpyrazine productsof this invention also forms part of the invention. Additionally, themethods by which the chlorinated methylpyrazines are converted to the3-aminopyrazinoate products and the method for preparing thepyrazinamide products also form part of this invention.

It was found that direct chlorination of 2-methyl-pyrazine could beeffected in acetic acid or in carbon tetrachloride at elevatedtemperatures preferably at an elevated temperature advantageouslybetween the reflux temperature of the reaction medium up to about 250 C.The number of chlorine atoms that become attached to the methylpyrazinestarting material is a function of the temperature employed as well asthe length of time the reaction is carried out; the longer the reactiontime and/or the higher the temperature the more chlorine atoms becomeattached.

The chlorinated methylpyrazines then can be converted to alkyl 3- orS-aminopyrazinoates which then are employed as described in U.S. Pat.No. 3,313,813 in the preparation of the therapeutically useful(3-aminopyrazinoyl)quanidines, by first reacting the chlorinatedmethylpyrazine with hydroxylamine. It was unexpectedly found thatinstead of a hydroxylamine derivative being formed, an amino derivativewas produced by this reaction. the amino substituent being attached tothe 5- position in relation to the methyl substituent. The reactionadvantageously is carried out in the presence of a solvent such asethanol under basic conditions. Best results are obtained when thereaction mixture is heated preferably at reflux temperature for a periodof from 1 to several hours. The 5-amino-2- (hydroxyliminomethyl) productobtained is acylated by treatment with an alkanoic anhydride and thenpyrolyzed to yield a 5-amino-2-cyanopyrazine. Acylation advantageouslyis conducted with cooling and is completed within a very short time,generally from a few minutes up to about 30 minutes. The productobtained then can be separated, if desired, and suspended in an inertmedium such as xylene and heated preferably to reflux from 1 to severalhours whereupon a 5- amino-2-cyanopyrazine is obtained. Hydrolysis ofthis product with strong mineral acid, preferably sulfuric acid,produces the corresponding amide which, upon addition of an alkanol oraralkanol forms the corresponding ester of 5- aminopyrazinoic acid. Whenthe chlorinated methylpyrazine starting material employed in thisreaction is 2-chloro-3- dichloromethylpyrazine the product obtained bythe reaction just described is an ester of 5-amino-3-chloropyrazinoate.The 3-chloro group then can be replaced by an amino group by reaction ofthis product with ammonia to form the ester of 3 ,5 diaminopyrazinoicacid which upon reaction with guanidine forms the diuretic product,(3,5-diaminopyrazinoyl) quanidine. Alternatively, the ester of5-amino-3- chloropyrazinoate can be treated with chlorine to form thedesired ester of 5-amino-3,6-dichloropyrazinoate which upon treatmentwith ammonia provides the ester of 3,5-diamino-6- chloropyrazinoic acid.Reaction of this ester with guanidine by the process described in U.S.Pat. No. 3,313,813 gives the (3 ,5 -diamino-o-chloropyrazinoyl)quanidine.

Other methods are described in the following Preparations" for preparing3-aminopyrazinoic acid esters from the novel chlorinated methylpyrazinesof this invention.

In the preparation of the pyrazinamide tuberculostatic and analepticagents of U.S. Pat. No. 2,149,279, the selected chlorinatedmethylpyrazine and in particular the 2- (trichloromethyl) pyrazinecompound is initially converted to an ester by the reaction of saidcompound with an alkanol to give the lower alkyl pyrazinoate. Thisproduct upon reaction with ammonia is readily converted to the desiredpyrazinamide or it can be reacted with hydrazine to form a pyrazinoicacid hydrazide product.

The preparation of the novel chlorinated methylpyrazines as well astheir use as intermediates in making the products described hereinaboveis more fully described in the following examples and preparations.

EXAMPLE 1 Analysis calculated for c H Cl N Cl(ionic)l4,7; C1(totall)29.0; N, 17.3; C1 (ionie)l5.0;

EXAMPLE 2 2-Chloro-3-(dichloromethy1)pyrazine A solution of 128.6 g.(1.0 mole) of 2-chloro-3-methylpyrazine in 900 ml. of glacial aceticacid is maintained at C. while chlorine is passed through the solutionat a rate of 10 mmole/min. for 4 hours. The reaction solution is cooledto 25 Found: C. 49.6; H, 3.6;

Analysis calculated for C,H- .CI,N,:

C. 30.4; H. 1.5; Found: C. 30.6; H. 1.4;

Cl. 53.9; N. 14.2; CI. 54.1; N. 14.4.

EXAMPLE 3 2-Chloro-3-(dichloromethyl)pyrazine and3,5-Dichloro-2-(dichloromethyl)pyrazine 2-Chloro-3-methylpyrazine (27.71g., 0.215 mole) and chlorine (65 g., 0.9 mole) in 250 ml. of acetic acidis heated in a closed vessel at 100 C. for 3 hours. The acetic acid isremoved at reduced pressure and the residual oil dissolved in 200 ml. ofchloroform, washed with 200 ml. of water and 200 ml. of percent sodiumbicarbonate solution and dried over sodium sulfate. Removal of thechloroform at reduced pressure, after filtration leaves 26.84 g. of ayellow oil which contains 8.1 g., 25 percent of theory, of 2-chloro-3-(dichloromethy1)pyrazine and 16.1 g., 32 percent of theory, of3,5-dichloro2-(dichloromethyl)pyrazine by VPC. The latter component canbe isolated by fractional crystallization and recrystallized frompetroleum ether to give white needles: m.p. 53.5-54.5 C.; UV (Cl-1 01i)A% 286 at 290 mu, A% 311 at 283 mu, A% 470 at 225 mu.

Analysis calculated for C,H,CI.N,:

C. 25.9; H. 0.9; Found: C. 26.1; H, 0.8;

EXAMPLE 4 cent of theory of 2-(trichloromethyl)pyrazine: m.p. 38-39 C.;UV (Cl-[ 011) A% 33.5 at 310 mu, A% 354 at 266 mu.

Analysis calculated for C,H;CI .,N,:

C. 30.4; H. 1.5; Found: C. 30.3; H. 1.3;

Cl. 53.9; N. 14.2; C1. 53.8;N,13.9

EXAMPLE 5 5-Ch1oro-2-(trich1oromethyl)pyrazine and6-Chloro-2-(trichloromethyl)pyrazine A solution of 5.00 g. (25.3 mmoles)of 2- (trichloromethyl)pyrazine from example 4 and 12 g. (170 mmole) ofchlorine in 50 ml. of carbon tetrachloride is heated at 200 C. for 5hours. Removal of the carbon tetrachloride at reduced pressure, aftertreatment of the reaction solution with 0.5 g. of decolorizing charcoalgives an oily crude product which is shown by VPC to contain 1.8 g. (30percent) of 6- chloro-2-(trichloromethyl)pyrazine, and 1.3 g. (22percent) of 5-chloro-2-(trichloromethyl)pyrazine. The latter isomercrystallizes spontaneously in the crude product mixture and isrecrystallized from petroleum ether to form white needles: m.p. 76-77C.; UV (CH Ol-1) A% 337 at 278 mu, A% 325 at 275 mu, A% 441 at 219 mu.

Analysis calculated for C,H,CI.N,:

C. 25.9; H. 0.9; Found: C. 26.2; H. 1.0;

CI. 61.2;N. 12.1; Cl.6l.5;N. 11.9.

EXAMPLE 6 2-Chloro-3-( trichloromethyl )pyrazine A solution of 6.12 g.(47.6 mmole) of 2-chloro3-methylpyrazine and 27 g. (380 mmole) ofchlorine in 50 ml. of carbon tetrachloride is heated at 200 C. for 5hours. Removal of the carbon tetrachloride at reduced pressure gives anorange oil which as shown by VPC contains 5.3 g. (64 percent) of 2-chloro-3-(trich1oromethyl)pyrazine. Purification by preparative VPC,provides the product as a colorless liquid at room temperature: UV (CHOH) A% 284 at 274 mu, A% 272 at 270 mu, A% 323 at 220 mu.

Analysis calculated for C H,Cl.N,

C. 25.9; H. 0.9; Found: C. 25.6; H. 0.7;

Cl. 61.2; N. 12.1; CI. 60.1; N. 12.2.

EXAMPLE 7 Analysis calculated for C.,HCl,N,:

' C, 20.6; H. 0.3; Found: C. 21.0; H. 0.3;

CI. 71.1; N. 8.0; CI. 70.7; N. 8.0.

Removal of the petroleum ether from the mother liquor gives an oil whichis shown by VPC to contain 9.8 g. (27 percent) of2,3-dichloro-5(trichloromethyl)pyrazine. Purification by VPC providesthe product as a colorless oil. UV (CH -,OH) A% 274 at 293 mu, A% 276 at281 mu, A% 354 at 225 m Analysis calculated for C .,HC1,N,:

c. 22.6; H, 0.4; CI. 66.6; N. 105;

Found: c, 22.7; H,0.3; CI. 66.6; N. 10.9.2.3-Dich1oro-5-(trichloromethyl)pyrazine can also be prepared in greateryield by the direct chlorination of 2- (trichloromethyl)pyrazine incarbon tetrachloride solution at 240-250 C.

USE OF CHLORlNATED METHYLPYRAZINES AS INTERMEDIATES Preparation 1 (3.S-Diamino-6-chloropyrazinoyl )guanidine Step A: Preparation of5-amino-3-chloro-2-(hydroxyiminomethyl)pyrazine A solution of 221 g.(3.20 mole) of hydroxylamine hydrochloride in 640 ml. of water and 640ml. of ethanol is buffered to pH 7.5 with 10M sodium hydroxide solution(requires ca. 300 ml. To this is added 63.2 g. (0.320 mole) of2-chloro-3-(dichloromethyl)pyrazine (product of example 3) and thereaction mixture is refluxed for 5 hours. At the end of this period 280ml. of solvent is distilled from the reaction solution which then isstored overnight in a refrigerator at 0-10 C. The resulting orange-browncrystals are filtered, washed with ml. of water and dried under reducedpressure at 100 C. to afford 18.1 g. (32.8 percent) of 5-amino-3-chloro-2-(hydroxyiminomethyl)pyrazine: m.p. 222-223 C. (dec.); UV (Cl-1011) A% 495 at 348 mu, A% 1207 at 283 mu.

CI. 20.5; N. 32.5; C1. 20.5; N. 32.3.

Step B: Preparation of 5-amino-3-chloro-2-cyanopyrazine To a vigorouslystirred solution of 18.1 g. (0.105 mole) ofamino-3-chloro-2(hydroxyiminomethyl)pyrazine in 400 ml. of 1.0M sodiumhydroxide is added 40 ml. of acetic anhydride dropwise over a 20 minuteperiod. The temperature of the reaction mixture is maintained at 20-25C. using a cooling bath throughout the addition period. After stirringfor an additional minutes the precipitate is filtered, washed thoroughlywith 300 m1. of water and dried at 80 C. at reduced pressure to yield21.5 g. (95 percent) of crude 5-amino-3chloro-2-(acetoxyiminomethyl)pyrazine: m.p. 194-l97 C. (dec.), UV(CH O1-1) A% 474 at 347.5 mp, A% 1167 at 283 mp..

After grinding to a fine powder the crude acetate is suspended in 1liter of xylene and vigorously stirred throughout a 16 hour refluxperiod. Decolorizing charcoal (0.50 g.) then is added to the hot xylenesolution and the mixture then filtered. The yellow filtrate is stored inthe refrigerator for 6 hours and the resulting yellow crystals removedby filtration, washed with 200 ml. of n-hexane and dried under reducedpressure at 80 C. to afford l 1.7 g. (72 percent based on oxime) of5-amino-3-chloro-2-cyanopyrazine: m.p. 16ll64 C.; UV (Cl-1 014) A% 495at 327 my, A% 1329 at 272 my.

Analysis calculated for C,H,N,Cl:

C, 38.9; H, 2.0; N. 36.3; Found: C, 39.2; H, 2.1; N, 36.6.

Step C: Preparation of methyl 5-amino-3-chloro-2 pyrazinoate A solutionof 5.00 g. (32.3 mmole) of 5-amino-3-chloro-2- cyanopyrazine in 10 ml.of concentrated sulfuric acid is heated on a steam bath for 35 minutesand then added to 500 ml. of absolute methanol and refluxed for hours.The resulting solution is treated with 1.0 g. of decolorizing charcoal,filtered, concentrated to 300 ml. and cooled thereby affording methyl5-amino-3chloropyrazinoate as yellow needles which are filtered, washedwith 10 ml. of methanol and dried at 100 C. under vacuum. The yield ofproduct is 3.45 g. (57 percent): m.p. 245-248 C. (dec.) UV (Cl-1 011) A%486 at 322.5 mg, 920 at 274 mi.

Analysis calculated for C,,H,,C1N,O,:

c. 38.4; H. 3.2; c1,1s.9;-.22.4; Found: c. 33.5; H, 3.1; CI. 18.8; N.22.2.

Step D: Preparation of methyl 5-amino-3,6-dichloro-2- pyrazinoate Aslurry of 1.00 g. (5.33 mmole) of methyl 5-amino-3- chloro-Z-pyrazinoatein 20 ml. of acetonitrile is maintained at 6065 C. for an additional 70minutes. After cooling to room temperature the solid material isfiltered, washed with 2 ml. of acetonitrile, dried and recrystallizedfrom methanol-water to afford 0.51 g. (43 percent) of methyl5-amino-3,6-dichloro-2 pyrazinoate as yellowish needles: m.p. 186-187C.; UV (CH OH) A% 437 at 326 mu, A% 697 at 273 mp.

Analysis calculated for C,,H,,CI,N,O,:

C. 32.5; H. 2.3; CI. 31.9;N.18.9; Found: C. 32.9; H. 2.1; CI. 32.2; N,19.4.

Step E: Preparation of methyl 3,5-diamino-6-chloro-2- pyrazinoate Asolution of 0.20 g. (0.90 mmole) of methyl 5-amino-3,6-dichloro-2-pyrazinoate in 4 ml. of dimethyl sulfoxide is heated at 125C. for 4 hours while anhydrous ammonia is bubbled into the reactionmixture. Addition of 5 ml. of water produces yellow needles which arefiltered, washed with water, dried and recrystallized from acetonitrileto afford 0.08 g. (44 percent) of methyl3,5-diamino-6-chloro-2-pyrazinoate, m.p. 207-208.5 C., identical bymixture melting point, 1R, UV, TLC and VPC with an authentic sample.Step F: Preparation of chloropyrazinoyl)quanidine The ester obtained instep E is reacted with guanidine according to the procedure described inU.S. Pat. No. 3,313,813, example 79, to give (3,5-diamino-6-chloropyrazinoyl)guanidine, m.p. 240.5241.5 C. (dec.).

(3 .5-diamino-6- Preparation 2 (3,5-Diamino-6-chloropyrazinoyl)guanidine Step A: Preparation of 3-chloropyrazinoic acid2-Chloro-3-(chloromethyl)pyrazine (0.1 mole). product of example 1, isdissolved in 12 ml. of concentrated sulfuric acid and 28 ml. of water.The solution is boiled under reflux for 15 hours under nitrogen andtreated with 34 ml. of concentrated nitric acid (70 percent) and 0.1 g.of ammonium vanadate and heated at C. for 24 hours. The mixture isconcentrated in vacuo to a syrup, diluted with 25 ml. of water and thepH adjusted to 1 with concentrated ammonia with cooling. The 3-chloropyrazinoic acid is collected on a filter, washed with water anddried. Step B: Preparation of 3-aminopyraziznoic acid A mixture of 1.58g. (10.0 mmole) of 3-chloropyrazinoic acid in 25 ml. of anhydrousammonia is heated at C. for 5 hours. Evaporation of the ammonia leaves awhite solid which upon solution in 20 ml. of water and acidificationwith 0.5 ml. of 12 N hydrochloric acid affords 3-aminopyrazinoic acid(0.75 g., 5.4 mmole, 54 percent) after filtration and drying, m.p.202-23.5 C. (dec.).

Step C: Preparation of methyl 3-aminopyrazinoate.

To a solution prepared by passing dry hydrogen chloride gas into chilledanhydrous methanol is added the 3- aminopyrazinoic acid product of stepB in the form of a finely ground powder. The resulting suspension isstirred at room temperature for about 24 hours, the reaction mixturethen concentrated under reduced pressure to about half its volume andthe residue poured into ice water. The insoluble hydrochloride salt iscollected and treated with aqueous sodium bicarbonate solution, withgood stirring, to provide methyl S-aminopyrazinoate.

Step D: Preparation chloropyrazinoyl)quanadine The methyl3-aminopyrazinoate obtained as described above is first converted tomethyl 3-amino-5,6- dichloropyrazinoate then this product is amidated toform methyl 3,5-diamino-6-chloropyrazinoate which in turn is reactedwith guanidine to provide (3,5diamino-6- chloropyrazinoyl)guanidine bythe procedures described in U.S. Pat. No. 3,313,813, examples I and 76.

of (3,5-diamino-6- PREPARATlON 3 Pyrazinoic Acid Amide Step A:Preparation of methyl Z-pyrazinoate A solution of2-(trichloromethy1)pyrazine (1.98 g., 10 mmole), a product of example 4,in 50 ml. of methanol is refluxed for 17.5 hours. After concentration to23 ml. the reaction solution is shaken with 50 ml. of water and 50 ml.of ether. After separation, the ether layer is dried over magnesiumsulfate, filtered and concentrated to give methyl 2- pyrazinoate shownby VPC analysis and IR and NMR (nuclear magnetic resonance) spectra tobe identical with an authentic sample of methyl 2-pyrazinoate. Step 13:Preparation of pyrazinoic acid amide The methyl 2-pyrazinoate obtainedas described above is dissolved in methanol and treated with amethanolic solution of ammonia as described in U.S. Pat. No. 2,149,279to provide the desired pyrazinoic acid amide product.

PREPARATION 4 (3-Aminopyrazinoyl)guanidine Step A: Preparation of methyl3-chloropyrazinoate A solution of 2-chloro-3-(trichloromethyl)pyrazine(0.1 mole) in 600 ml. of methanol is refluxed for 18 hours, cooled,diluted with 600 m1. of water and extracted with ether. The ether layeris washed with water, dried over magnesium sulfate and concentrated todryness to give methyl 3- chloropyrazinoate. Step B: Preparation ofmethyl 3-aminopyrazinoate By replacing the methyl3,6-dichloro'5-aminopyrazinoate employed in preparation 1, step E, by anequimolecular quantity of the methyl 3-chloropyrazinoate obtained asdescribed above and following substantially the same procedure describedin preparation 1, step E, there is obtained methyl 3- aminopyrazinoate.

Step C: Preparation of 3-aminopyrazinoyl)guanidine By replacing themethyl 3,5-diamino-6-chloropyrazinoate employed in preparation 1, stepF, by an equimolecular quantity of methyl 3-aminopyrazinoate andfollowing substantially the same procedures specified in step F ofpreparation 1 there is obtained (3-aminopyrazinoyl )guanidine.

PREPARATION 5 (3,5-Diamino-6chloropyrazinoyl)guanidine Step A:Preparation of methyl S-chloropyrazinoate By replacing theZ-trichloromethylpyrazine employed in preparation 3, step A, by anequimolecular quantity of 5- chloro-2trichloromethylpyrazine, theproduct of example 6 and following substantially the same proceduredescribed in preparation 3, step A, there is obtained methyl 5-chloropyrazinoate. Step B: Preparation of 5-chloropyrazinoic acid Asuspension of methyl S-chloropyrazinoate (4l mmole) in 50 ml. of l.25Nsodium hydroxide is shaken until solution results. The solution then isacidified with 10 ml. of concentrated hydrochloric acid and theresulting precipitate is filtered and dried yielding 5-chloropyrazinoicacid. Step C: Preparation of S-aminopyrazinoic acid A mixture of5-chloropyrazinoic acid l mmole) in 25 ml. of anhydrous ammonia isheated at 100 C. for about hours. Evaporation of the ammonia leaves asolid which upon solution in 20 ml. of water and acidification with 0.5ml. of l2N hydrochloric acid gives S-aminopyrazinoic acid. Step D:Preparation of methyl S-aminopyrazinoate Fuming sulfuric acid (65percent, 0.l8 mole) is cautiously added to 12 g. of methanol whilekeeping the temperature below 50 C. The solution is cooled to 25 C. and30 g. of 5- aminopyrazinoic acid is added. The solution then is heatedat 50 C. for 2% hours, cooled to 25 C. poured onto 150 g. of ice andneutralized to pH 6 with l5N ammonium hydroxide keeping the temperaturebelow 40 C. to give methyl 5- aminopyrazinoate which is separated byfiltration and then washed with water. Step E: Preparationaminopyrazinoate A slurry of methyl S-aminopyrazinoate (0.1 mole) in 400ml. of acetonitrile is heated at 60C. while chlorine (4.2 mole) ispassed in over a period of minutes. The mixture then is heated at 60 C.for l hour, cooled to 0-5 C. and filtered to give methyl3,6-dichloro-5-aminopyrazinoate. Step F: Preparation ofchloropyrazinoyl)guanidine By replacing the methyl3,o-dichloro-S-aminopyrazinoate employed in step E of preparation I bythe methyl 3,6- dichloro-S-aminopyrazinoate obtained as described above,and then following substantially the same procedures specified in stepsE and F of preparation 1, there is obtained (3,5-diamino-6-chloropyrazinoyl)guanidine.

of methyl 3,6-dichloro-5- (3,S-diamino-6 PREPARATION 6 obtained asdescribed above and then following substantiall the same proceduredescribed In preparation 5, steps through D, there is obtained methyl5-amino-6- chloropyrazinoate. Step C: Preparation of methyl3,6-dichloro-5 aminopyrazinoate By replacing the methylS-aminopyrazinoate employed in preparation 5, step E, by methyl5-amino-6-chloropyrazinoate and following substantially the sameprocedure described in preparation 5. step E, with the exception thatonly 0.1 mole of chlorine is employed, there is obtained methyl3,6-dichloro-5- aminopyrazinoate. It will be recognized that this is thesame product as is obtained in preparation 5, step E.

While the above examples describe the preparation of cer tain novelchlorinated methylpyrazine products of this invention and the use ofthese novel chlorinated methylpyrazines in the preparation oftherapeutically active 3-aminopyrazinoyl guanidine products, and apyrazinamido product, is to be understood that the invention is not tobe limited to the particular methods described but is to be understoodto embrace obvious equivalents thereof within the knowledge of thoseskilled in the art.

What is claimed is:

l. The reaction of a product selected from methylpyrazine or achlorinated methylpyrazine and chlorine in the presence of a solventselected from acetic acid and carbon tetrachloride and at a temperaturebetween reflux temperature and about 250 C. to provide a chlorinatedmethylpyrazine having the structure wherein m represents the numeralstwo through five and n is zero or one, with the proviso that when n isone, the (C Cl group is a nuclear substituent.

2. A modification of the process claimed in claim 1, wherein thechlorinated methylpyrazine product obtained is caused to react withhydroxylamine to provide a 5-amino-2-(hydroxyiminomethyl)pyrazine.

3. A process as claimed in claim 2, wherein the reaction mixture isheated at about reflux temperature.

4. A process as claimed in claims 2 or 3 wherein 2-chloro-3-(dichloromethyl)pyrazine and hydroxylamine are caused to react toprovide 5-amino-3-chloro-2-(hydroxyiminomethyl )pyrazine.

2. A modification of the process claimed in claim 1, wherein thechlorinated methylpyrazine product obtained is caused to react withhydroxylamine to provide a 5-amino-2-(hydroxyiminomethyl)pyrazine.
 3. Aprocess as claimed in claim 2, wherein the reaction mixture is heated atabout reflux temperature.
 4. A process as claimed in claims 2 or 3wherein 2-chloro-3-(dichloromethyl)pyrazine and hydroxylamine are causedto react to provide 5-amino-3-chloro-2-(hydroxyiminomethyl)pyrazine.